Cell encapsulation loading device

ABSTRACT

The present invention provides a loading fixture for loading cells, cell clusters, and media to an immune-isolation device. The loading fixture permits the loading of cells into the immune-isolation device without manual manipulation of the immune-isolation device, until the loading device is opened at the point of use, thereby minimizing the risk of contamination of the immune-isolation device.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional of U.S. application Ser. No.15/047,027, filed Feb. 18, 2016, and which claims the benefit of U.S.Provisional Patent Application Ser. No. 62/117,974, filed Feb. 19, 2015,all of which are incorporated herein by reference in their entirety forall purpose.

FIELD OF THE INVENTION

The invention relates to the field of loading devices useful in loadingcells into an encapsulation device. In particular, the invention relatesto devices for loading cells into a medical device that will beimplanted into a body.

BACKGROUND

There is a clinical need for devices that encapsulate living cells andallow transplantation into a host without triggering a robust immuneresponse from the host. In general, cellular material harvested from oneanimal and implanted in another, even of the same species, will beattacked and destroyed by the host's immune response. In the case oforgan transplants, immunosuppressive drugs are needed to prevent organrejection. Otherwise, organ and tissue transplantation would almostalways cause an immune response and result in destruction of thetransplanted tissue.

However, it is possible to construct a device to encapsulate tissue orcells to eliminate the need for immunosuppressive drugs. Such a devicetypically is constructed of porous material allowing for the necessaryexchange of metabolites, nutrients and waste products between the celland the host. At the same time, the porosity of the material iscontrolled to isolate the interior of the device from invasion from thehost immune system, including phagocytes.

After the device is loaded with living cells, it is implanted into ahost body. It is important that the vasculature of the host grows intointimate contact with the exterior surface of the device so that bloodvessels can facilitate the exchange of metabolites with the encapsulatedcells through perfusion. The transplanted living cells must be in closeproximity to the host blood vessels to ensure their continued survivaland functioning. Therefore, loading of the cells within the device sothat the cells are in proximity to the blood vessels is of primaryimportance. Additionally, loading of the cells must be carried out in amanner that minimizes trauma to the cells so that therapeutic amounts ofthe cells survive loading into the device.

Another factor to be considered in cell loading is that, in currentpractices, significant manual manipulation of the immune-isolationdevice (“IID”) in an “open” sterile environment using aseptic steriletechniques is required. Although this open air environment is sterile,manual manipulation of the IID under these conditions is undesirable dueto the increased risk of contamination by unwanted microorganisms.

Therefore, there is a need for a loading fixture and method for loadingthat ensures the desired placement of the cells within the device andminimizes trauma to the cells while reducing or substantiallyeliminating the manual manipulation of the IID thereby reducing the riskof contamination of the implantable device.

SUMMARY

In one embodiment, the invention provides a loading device comprising abase, a disk lid, having a luer adapter fixedly attached thereto, a snaplid, wherein the disk lid and snap lid form a cavity in the base, ablade ring assembly slidably connected to the base, a junction blockfixedly attached to the base and having a luer adapter fixedly attachedthereto, and a barb, and a barb pusher slideably connected therein.

In some embodiments, the loading device further comprises animmune-isolation device having an inlet tube and a cell pouch insertedwithin the cavity wherein the cell pouch rests on the base and the inlettube is inserted through the junction block.

In other embodiments, the invention provides for methods of using theloading device comprising: (a) providing a loading device comprising abase, a disk lid, having a luer adapter fixedly attached thereto, a snaplid, wherein the disk lid and snap lid form a cavity in the base, ablade ring assembly slidably connected to the base, a junction blockfixedly attached to the base and having a luer adapter fixedly attachedthereto, a barb, and a barb pusher slideably connected therein, and animmune-isolation device comprising an inlet tube and a cell pouchinserted within the cavity wherein the cell pouch rests on the base andthe inlet tube is inserted through the junction block; (b) sterilizingthe loading device, optionally, wetting the cell pouch with hydrophilicliquid; (c) filling the cell pouch with cells and the cavity with cellmedia; (d) sealing the inlet tube with the barb; (d) closing the loadingdevice; (e) transporting the loading device to the point of use; (f)opening the loading by rotating the disk lid counter-clockwise, therebycutting the inlet tube; and (g) removing the cell pouch from the loadingdevice at the point of use.

In another embodiment, the invention provides for a system for loadingimmune-isolation devices comprising: a base having a base bottom surfaceand a base wall extending from the base bottom surface to form a cavity;an inlet conduit positioned on the base and extending there through intothe cavity of the base; a disk lid removably attachable to the base toseal the cavity; and a blade having an edge slidably disposed within thecavity of the base, whereby the edge of the blade is configured to slidein front of the inlet conduit, and whereby the system is configured tobe vented.

In yet another embodiment, the invention provides for a method ofpreparing immune-isolation devices comprising: (a) providing a loadingsystem comprising a base having a base bottom surface and a base wallextending from the base bottom surface to form a cavity, an inletconduit positioned on the base and extending there through into thecavity, and a disk lid removably attachable to the base to seal thecavity; (b) coupling an immune-isolation device, comprising an inlettube attached to a pouch, to the inlet conduit positioned on the basewithin the cavity; (c) sealing the cavity with the disk lid; (d) fillingthe pouch of the immune-isolation device with cells via the inletconduit; (e) filling the cavity with cell media; and (f) sealing theinlet tube.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a top perspective view of a loading device of the invention.

FIG. 1B is a top perspective view of the loading device of FIG. 1A withan exemplary immune-isolation device (“IID”).

FIG. 1C is an alternative top perspective view of the loading device andIID of FIG. 1B.

FIG. 2A is an exploded view of the loading device of FIG. 1A.

FIG. 2B is an exploded view of the loading device of FIG. 1B.

FIG. 3 is a side perspective view of a base of the loading device ofFIG. 1A.

FIG. 4 is a bottom perspective view of the base of FIG. 3.

FIG. 5 is a top plan view of the base of FIG. 3.

FIG. 6 is a top perspective view of a blade ring assembly of the deviceof FIG. 1A.

FIG. 7 is a top perspective view of a disk lid of the device of FIG. 1A.

FIG. 8 is a bottom perspective view of the disk lid of FIG. 7.

FIG. 9 is a top perspective view of a snap lid of the device of FIG. 1A.

FIG. 10 is a side view of a junction block of the device of FIG. 1A.

FIG. 11 is a side perspective view of a barb plug of the device of FIG.1A.

FIG. 12 is a side perspective view of a barb pusher assembly of thedevice of FIG. 1A.

FIG. 13 is an exploded view of an alternate embodiment of the base ofFIG. 3 with support plate.

FIG. 14 a top perspective view of a base of FIG. 13.

FIG. 15 is a bottom perspective view of the base of FIG. 13.

FIG. 16 is an alternate top perspective view of a base of FIG. 13.

FIG. 17 is a top perspective view of a support plate of FIG. 13.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of the invention will be betterunderstood when read in conjunction with the appended figures. For thepurpose of illustrating the invention, the figures demonstrateembodiments of the present invention. However, the invention is notlimited to the precise arrangements, examples, and instrumentalitiesshown.

The terms “proximal” and “distal” are used herein when describing theorientation of parts or components in relationship to one another. Forthe purposes of this disclosure, the proximal side is the side closestto the plunger 182 of the barb pusher assembly 46 (see FIG. 12) and thedistal side is the furthest from the plunger 182 of the barb pusherassembly 46 (see FIG. 12), when the loading device 20 is in an assembledconfiguration (see FIGS. 1A-1C and 2A-2B).

Shown in FIG. 1A is a loading device 20 of the invention. The device ofthe invention enables the user to load cells or cell clusters into animmune-isolation device (“IID”) 23 (FIG. 2B) held within device 20 (seealso FIGS. 1B and 1C). The IID 23 is an implantable medical device thatallows therapeutic cell products out of the device and simultaneouslyprotects the cells or cell clusters within the device from the host'simmune response. The device of the invention enables the user to loadcells or cell clusters into the IID 23 while minimizing theopportunities for contamination due to manual manipulation, minimizingcell trauma, and facilitating accurate placement of the cells within thedevice. Furthermore, the loading device 20 also may serve as thepackaging for transport and storage of the IID 23. The IID 23 preferablyis not removed from the loading device 20 until the point of use, forexample when the IID 23 in the loading device 20 arrives in the surgicalsuite and is ready for implantation. In a preferred embodiment, theloading device 20 allows a user to: wet the IID 23 with a hydrophilicliquid, rinse or soak the IID 23 in a aqueous solution to removeresidual hydrophilic liquid, load cells or cell clusters into the IID23, surround the IID 23 loaded with cells with media enabling the cellsto survive for a period of time, seal the IID 23, and finally open theloading device 20 at the point of use without tools to retrieve the IID23, all while maintaining sterility and reducing the risk ofcontamination.

An embodiment of the loading device 20 is shown in FIGS. 1A-1C and2A-2B. Loading device 20 includes a base 22 that is moveably connectedto blade ring assembly 24. O-ring 26 is seated between base 22 and disklid 28. A snap lid 30 is removably connected through disk lid 28 andfurthermore, snap lid 30 is removably attached to base 22 and, withO-ring 26, forms a seal between disk lid 28 and base 22. Disk lid 28interacts ratchetedly with blade ring assembly 24 when rotated in theclockwise direction and locked with blade ring assembly 24 when rotatedin the counter-clockwise direction. First luer fitting 32, with a firstluer cap 34 removably seated thereon, is fixedly attached to the topsurface of disk lid 28.

Loading device 20 also includes junction block 36 fixedly attached tobase 22. There are two tabs located at the distal end of the junctionblock 36. The locking tab 174 is on the top side of the junction block36 and extends upwardly. The latch tab 176 is on the bottom side of thejunction block 36 and extends downwardly as shown in FIG. 10. Latch tab176 is inserted into notch 90 in flange base 88 (see FIG. 3) and lockingtab 174 is secured by the junction block retention feature 142 on disklid 28 (see FIG. 8). Junction block seal 38 forms a compression sealbetween junction block 36 and base 22 thereby preventing fluids fromleaking out from between the junction block 36 and the base 22. Secondluer cap 40 is removably attached to the second luer fitting 166 onjunction block 36. Barb 44 is removably seated within barb plug 42 andbarb plug 42 is removably seated within junction block 36. The barb plug42 forms a compression seal against the interior of the junction block36 on the outside of the barb plug 42 and against the barb 44 on theinside of the barb plug 42, thereby preventing fluids that are exitingor entering the loading device 20 through the second luer fitting 166 onthe junction block 36 from leaking into the junction block 36. Barbpusher assembly 46 is movably inserted within junction block 36 and heldin place by retainer pin 48 and safety pin 50. Retainer pin 48 preventsthe barb pusher assembly 46 from coming out of the junction block 36 andsafety pin 50 prevents the barb pusher assembly 46 from sliding furtherinto the junction block 36 prematurely. The barb pusher assembly 46serves as a means to push the barb 44 into the inlet tube and seal theIID 23. An exemplary IID 23 is shown in FIGS. 1B, 1C, and 2B.

In FIG. 3 is shown a perspective view of a base 22. The base 22 has abase surface loft 60 (also see alternate view in FIG. 5), a base bottomsurface 62 and a base wall 64 therearound. Base wall 64 includes baseinner wall 66 and base outer wall 68, with an O-ring channel 70 formedin the top surface of the base wall 64. O-ring 26 is removably seated inO-ring channel 70. The base surface loft 60 and base wall 64 form acavity 72 as shown. Base 22 also includes at least one junction blockflange 76, a plurality of feet 78, a plurality of tab ramps 80, a tabramp stop 82, and a snap lid stop 84. The junction block flange 76 ispreferably located at the intersection of the base bottom surface 62 andthe base outer wall 68. The junction block flange 76 has two flangesides 86, one flange base 88 between the flange sides 86, and notch 90within flange base 88. The plurality of feet 78 extend outwardly fromthe base outer wall 68, and preferably are located at the intersectionof the base bottom surface 62 and the base outer wall 68 and areuniformly distributed around the circumference of the base 22 as shown.In one embodiment, there are at least two feet 78. In anotherembodiment, there are four feet 78, but any convenient number may beused. Similarly, there are a plurality of tab ramps 80 located at thetop edge of the base outer wall 68 extending outwardly from base outerwall 68 and uniformly distributed about the circumference of the base 22as shown, with the first tab ramp 92 aligned with one flange side 86,and the last tab ramp 94 having a tab ramp stop 82. The tab ramps 80increase in width in the clockwise direction such that, when the tabramps 80 are engaged by snaps 156 (see FIG. 9) as the disk lid 28 (seeFIG. 8) is rotated clockwise, simultaneously the O-ring 26 forms a sealbetween the disk lid 28 and base 22 such that fluids may not leak out ofthe loading device 20. The tab ramp stop 82 prevents excessive clockwiserotation, by limiting travel length, of the disk lid 28 and snap lid 30(see FIG. 9), thereby preventing the snaps 156 of snap lid 30 fromdisengaging from the tab ramps 80 on base 22. In one embodiment, thereare at least four tab ramps 80. In another embodiment, there are six tabramps 80. Again, any convenient number may be used. The snap lid stop 84is aligned with one flange side 86 and the top edge of the base outerwall 68. Furthermore, the snap lid stop 84 is positioned between thelast tab ramp 94 and the junction block flange 76, such that the snaplid stop 84 limits counter-clockwise rotation of the snap lid 30 anddisk lid 28, thereby preventing the snaps 156 on snap lid 30 fromre-engaging the adjacent tab ramp 80 and enabling opening of the loadingdevice 20 to gain access to the IID 23.

FIG. 4 shows a bottom perspective view of base 22. This view shows thebase bottom surface 62 further has recessed base bottom 63 therein. Therecessed base bottom 63 reflects the underside of base surface loft 60,and has base bottom surface 62 therearound. The handle 74 is fixedlyattached to the recessed base bottom 63 along the length of the handle74. Handle 74 extends downwardly from recessed base bottom 63. Handle 74may be formed, for example by molding, into recessed base bottom 63.Handle 74 is useful for stabilizing the loading device 20, for examplefor stabilizing within the packaging, and providing features with whichto grasp the loading device 20 when opening to retrieve the IID 23.

FIG. 5 shows a top view of base 22 showing base surface loft 60 and basewall 64 therearound with a recessed blade ring channel 96 formed betweenthe base surface loft 60 and base wall 64. Base wall 64 includes, baseinner wall 66 and base outer wall 68, with an O-ring channel 70 formedin the top surface of the base wall 64. The base surface loft 60, whilesubstantially flat, slopes down slightly with the high point 65 oppositethe IID receiver 104. The slope of the base surface loft 60 is selectedso that it maintains a uniform spacing with the lid floor bottom 144 ofthe disk lid 28 (see FIG. 8) when removably attached to base 22. Therecessed blade ring channel 96 further has a blade ring stop 98, and ablade ring support 100. The blade ring stop 98 and blade ring support100 are located in the recessed blade ring channel 96. The blade ringsupport 100 is approximately aligned with flange side 86 and snap lidstop 84. The blade ring stop 98 is positioned in the recessed blade ringchannel 96, such that the blade ring end 116 (shown in FIG. 6) sitsagainst the blade ring stop 98 and the blade end 118 sits on the bladering support 100. The base wall 64 has an inlet tube conduit 102 on thebase inner wall 66 and exiting on the base outer wall 68 (not shown).The inlet tube conduit 102 is approximately centered on the base wall 64above the junction of the base wall 64 and the recessed blade ringchannel 96, and within the junction block flange 76. Inlet tube conduit102 is positioned on the base wall 64 such that when the IID 23 isseated on the base surface loft 60, the inlet tube of the IID 23 extendsthrough inlet tube conduit 102 and into the junction block 36 (see FIG.2B). The base surface loft 60 also has an IID receiver 104 on the basesurface loft 60 and in line with the inlet tube conduit 102. The IIDreceiver 104 is a cut out that provides relief (or clearance space) forthe attachment point between the inlet tube of the IID 23 and the cellpouch of the IID 23 such that the inlet tube of the IID 23 is notcompressed during assembly of the loading device 20. The IID assemblyaid 106 identifies the outline of the IID 23 as it sits on the basesurface loft 60. The inlet tube of IID 23 (see FIG. 1B) extends throughthe inlet tube conduit 102 and the proximal end of the cell pouch of theIID 23 (see FIG. 1C) sits in the IID receiver 104.

Base 22 may be made by any known manner, but conveniently may be made inone piece using methods known to those of skill in the art ofmanufacturing plastic parts. The base 22 may be prepared from polymerssuitable for medical use, such as medical grade polymers. The polymershould be rigid to maintain shape, withstand vacuum or pressure,moldable, translucent, and sterilizable. Suitable polymers, such asthermoplastic polymers, include but are not limited to polycarbonate,acrylonitrile butadiene styrene, polypropylene, polymethylmethacrylate,and the like. In one embodiment, the polymer is polycarbonate. The base22 may be produced using various known methods in the art, including butnot limited to molding, machining, and rapid prototyping such as,stereolithography, selective laser sintering, and the like.

FIG. 6 depicts blade ring assembly 24 that is a semi-circular, flexiblestructure that includes blade ring 108 and blade 110. Blade ring 108 hasa blade ring wall 112, a top edge 114, a blade ring end 116, and a bladeend 118. The blade ring 108 terminates at one end in blade post 120 andat the other, in blade ring end 116. Adjacent to blade post 120 andpositioned in top edge 114 are teeth 122 that end at spacer 124,adjacently located to teeth 122. The blade end 118 may be tapered forflexibility. Furthermore, blade ring assembly 24 has a blade ringopening 126.

The blade ring assembly 24 is prepared from two parts, a blade 110 and ablade ring 108. The blade 110 is made from a corrosion resistantmaterial of sufficient rigidity with which to cut. In one embodiment,the blade 110 is made from surgical grade steel. The blade 110 isdesigned and custom made using known machining and grinding methods toproduce a cutting edge. The blade ring 108 is prepared in one piecesimilarly to the base 22. The blade ring 108 and blade 110 may beassembled by a process known in the art as heat staking, where the blade110 is slid onto the blade post 120 and then the blade post 120 ismelted to secure the blade 110 to the blade ring 108. Heat staking isperformed at a temperature sufficient to melt the blade post 120.Alternately, the blade 110 may be overmolded into the blade ring 108 ormechanically attached using snap features and the like. In anotherembodiment, the blade 110 is eliminated entirely and the cutting edge isapplied to the blade end 118 of the blade ring 108 itself.

FIGS. 7 and 8 show a top view and bottom view of a disk lid 28,respectively. The top view of the disk lid 28 shows a disk lid outerwall 128 having a plurality of grooves 130 therein, and a flange 132extending inwardly from inner surface 127 of disk lid outer wall 128.Flange 132 has a plurality of snap lid holes 134 therein. In oneembodiment, there are at least four snap lid holes 134. In anotherembodiment, there are six snap lid holes 134. While any number of snaplid holes 134 can be envisioned, the number of snap lid holes 134 shouldbe equivalent to the number of snaps 156 on snap lid 30. Inner floorwall 136 extends downwardly from flange 132 and connects flange 132terminating at lid floor 138 that extends inwardly from inner floor wall136. A luer fitting receiver 140 extends upwardly from lid floor 138 andis adjacent to inner floor wall 136. The bottom view of the disk lid 28as seen in FIG. 8 shows the junction block retention feature 142, whichis a flange extending downwardly from the under surface of flange 132.Also shown is lid floor bottom 144 having a blade ring retainer 146aligned with inner floor wall 136 (see FIG. 7) and extending downwardlyfrom lid floor bottom 144. Furthermore, the blade ring retainer 146 hasa cut out 150 aligned with the junction block retention feature 142 toprovide relief for the inlet tube of IID 23. When the loading device 20is assembled, blade ring retainer 146 connects slidably with blade ringwall 112 thereby ensuring that blade ring assembly 24 stays within therecessed blade ring channel 96 and also ensuring that lid teeth 148engage teeth 122 on the blade ring assembly 24. Lid teeth 148 arepositioned adjacent to cut out 150 and extend downwardly at theintersection of the outer floor wall 149 and the lid floor bottom 144.The lid teeth 148 connect ratchetedly with the teeth 122 on blade ringassembly 24 when the disk lid 28 is rotated clockwise, and snaps 156 onsnap lid 30 engage tab ramps 80 of base 22. The lid teeth 148 interlockwith teeth 122 when the disk lid 28 is rotated counter-clockwise, whichthen moves the blade ring assembly 24 counter-clockwise and enables thecutting of the inlet tube of IID 23 simultaneously. An opening for theluer fitting receiver 140 is also shown in lid floor bottom 144. The lidfloor bottom 144 while substantially flat slopes down to a desireddegree with the high point at the luer fitting receiver 140 opposite thecut out 150. The degree of slope of the lid floor bottom 144 preferablyis sufficient to encourage air bubbles toward the luer fitting receiver140 on the disk lid 28 such that the bubbles may be removed.

FIG. 9 shows a perspective view of snap lid 30. Snap lid 30 is a ringmember 152 having a ring outer wall 154, and a plurality of snaps 156protruding downwardly from one surface of the ring. In one embodiment,there are at least four snaps 156. In another embodiment, there are sixsnaps 156. In yet another embodiment, the number of snaps 156 is equalto the number of snap lid holes 134, which is equal to the number of tabramps 80. The snaps 156 are configured to be complementary to and fitthrough the snap lid holes 134 on disk lid 28 and removably engagecorresponding tab ramps 80 on base 22. The tab ramps 80 are engaged bysnaps 156 as the disk lid 28 is rotated clockwise; simultaneously theO-ring 26 forms a seal between the disk lid 28 and base 22 such thatfluids may not leak out of the loading device 20.

A side view of a junction block 36 is shown in FIG. 10. The junctionblock 36 has a pusher channel 158, that tapers into a barb plug channel160, that further narrows into a barb channel 162, which then widensinto the inlet tube channel 164, that together extend through the lengthof the junction block 36. A second luer fitting 166 connects downwardlyinto the barb channel 162. The pusher channel 158 also has two pinconduits extending horizontally through the width of the junction block36. The retainer pin conduit 168 is proximal to the safety pin conduit170 and both pin conduits are located adjacent to the pusher channelopening 172. There are two tabs located at the distal end of thejunction block 36. The locking tab 174 is on the top side of thejunction block 36 and extends upwardly. The latch tab 176 is on thebottom side of the junction block 36 and extends downwardly, as shown.Junction block 36 is fixedly attached to base 22 by disk lid 28. Latchtab 176 is inserted into notch 90 in flange base 88 (see FIG. 3).Junction block seal 38 is located between junction block 36 and base 22,and within junction block flange 76. Junction block seal 38 forms acompression seal between junction block 36 and base 22. Second luer cap40 is removably attached to the second luer fitting 166 on junctionblock 36 (see FIGS. 2A and 2B). Locking tab 174 is engaged by junctionblock retention feature 142 when the disk lid 28 is rotated clockwise,and, and snaps 156 on snap lid 30 engage tab ramps 80 of base 22. Thetab ramp stop 82 prevents excessive clockwise rotation of the disk lid28 and snap lid 30, thereby preventing the snaps 156 of snap lid 30 fromdisengaging from the tab ramps 80 on base 22. Similarly, snap lid stop84 limits counter-clockwise rotation of the snap lid 30 and disk lid 28,such that the snaps 156 on snap lid 30 do not re-engage the adjacent tabramp 80 and prevent opening of the loading device 20 when the loadingdevice 20 is being opened to gain access to the IID 23.

The disk lid 28, snap lid 30, and junction block 36 are all preparedaccording to the methods described above for base 22, each as one wholepart.

A perspective view of a barb plug 42 is shown in FIG. 11. The barb plug42 has a barb receiver channel 178 that runs the length of the barb plug42. The barb plug 42 holds the barb 44 within the barb receiver channel178 and is removably located within barb plug channel 160 of junctionblock 36 (see FIG. 10). The barb plug 42, as well as the O-ring 26, andjunction block seal 38 are all prepared from compliant materials, forexample elastomers, that will conform to the space provided and preventany fluid leaking from the loading device 20. In one embodiment, theelastomer may be polyurethane or a silicone elastomer. In anotherembodiment, the elastomer is a silicone elastomer. The elastomericmaterials are also able to undergo sterilization without being degradedor deformed.

A perspective view of a barb pusher assembly 46 is shown in FIG. 12. Thebarb pusher assembly 46 has wire pusher 180 on the distal end andplunger 182 on the proximal end. The plunger 182 has a plunger stop 184and a guide plane 186. Safety pin 50 is inserted into safety pin conduit170 on junction block 36. The barb pusher assembly 46 is inserted intothe pusher channel opening 172 of junction block 36 with guide plane 186facing upward until the plunger stop 184 meets the safety pin 50. Theretainer pin 48 is then inserted into the retainer pin conduit 168, onthe proximal side of plunger stop 184, thereby preventing the barbpusher assembly 46 from falling out of the junction block 36 (see alsoFIG. 10).

The barb pusher assembly 46 is designed and constructed with adequatecolumn strength to advance and seat the barb 44 into the IID 23. Thewire pusher 180 is prepared from corrosion resistant, medical grademetal and is of suitable strength to place the barb 44 withoutdeformation. Suitable metals include, but are not limited to stainlesssteel, cobalt-chromium alloys, titanium, and titanium alloys. In oneembodiment, the metal is stainless steel. The plunger 182 may be madefrom polymers suitable for medical use, for example the polymer shouldbe rigid to maintain shape and sterilizable. Suitable polymers include,but are not limited to polycarbonate, acrylonitrile butadiene styrene,polypropylene, polymethylmethacrylate, and the like. In one embodiment,the polymer is polycarbonate. The barb pusher assembly 46 may bemanufactured using known insert molding methods or other processes, suchas machining.

The retainer pin 48 and safety pin 50 are prepared from corrosionresistant, medical grade metal. Suitable metals include, but are notlimited to stainless steel, cobalt-chromium alloys, titanium, andtitanium alloys. In one embodiment, the metal is stainless steel.

The barb 44 may be prepared in a suitable shape and from suitablematerials that will provide a seal to prevent cells or cell clusters ormedia from leaking from the inlet tube of the IID 23. Suitable materialsinclude, but are not limited to elastomers or corrosion resistant,medical grade metals. Suitable elastomers include, but are not limitedto polyurethane or silicone elastomers. Suitable metals include, but arenot limited to stainless steel, cobalt-chromium alloys, titanium, andtitanium alloys. In one embodiment, the metal is titanium.

The loading device 20 is assembled by first installing an IID 23 into abase 22, inserting the inlet tube through the inlet tube conduit 102from the inside of the base 22. The IID 23 is aligned with the IIDassembly aid 106 and held in place while the junction block seal 38 isinstalled over the inlet tube. The junction block seal 38 is advancedover the inlet tube until the junction block seal 38 is against the baseouter wall 68 of the base 22. An ultraviolet light activated adhesive isthen applied to the inlet tube and the inlet tube is inserted into theinlet tube channel 164 of junction block 36. Latch tab 176 on junctionblock 36 is then engaged with notch 90 in flange base 88 of the base 22.A UV light source is then activated shining through the side of theclear plastic junction block 36 to cure the UV adhesive within while thecomponents are held in place. The UV adhesive secures the inlet tubewithin the inlet tube conduit 102, thereby holding the IID 23 in placeduring the cell loading process. Suitable UV adhesives are solvent free,flexible, rapid curing, and compatible with the polymer components ofthe loading device 20. Blade ring assembly 24 is then inserted in therecessed blade ring channel 96 with the blade ring end 116 against theblade ring stop 98 and the blade end 118 on the blade ring support 100.The O-ring 26 is disposed in the O-ring channel 70. The disk lid 28 isthen secured to the base 22 using the snap lid 30. The snaps 156 on snaplid 30 feed through the snap lid holes 134 on disk lid 28, the snap lid30 is recessed in the disk lid 28, and snaps 156 engage the tab ramps 80while rotating the disk lid clockwise onto base 22. The disk lid 28 isturned clockwise such that the lid teeth 148 ratchetedly engage theteeth 122 on the blade ring assembly 24 and the junction block retentionfeature 142 engages locking tab 174 thereby securing the junction block36 in place within junction block flange 76. The barb 44 is loaded intothe barb receiver channel 178 within barb plug 42 and barb plug 42 isseated into the barb plug channel 160. The barb pusher assembly 46 isthen inserted into the pusher channel 158 of junction block 36 with thewire pusher 180 sliding into the barb receiver channel 178 within thebarb plug 42. The barb pusher assembly 46 is held in place within thejunction block 36 by placing the safety pin 50 in safety pin conduit 170and placing the retainer pin 48 in retainer pin conduit 170. The safetypin 50 prevents premature placement of the barb 44 in the inlet tube ofthe IID 23 and the retainer pin 48 prevents the barb pusher assembly 46from coming out of the junction block 36. Lastly, the loading device 20is closed using first and second luer caps 34 and 40, to close the firstand second luer fittings 32 and 166, respectively.

Once assembled, the loading device 20 is sterilized and ready to use.The loading device 20 is sterilized using techniques known to those ofskill in the art of sterilization, such as gamma sterilization, e-beamsterilization, and ethylene oxide sterilization. The loading device 20may be sterilized using any of the previously described techniques,however since the IID 23 is sterilized in the loading device 20 thematerials used to prepare the IID 23 must be considered when selecting asterilization technique. In one embodiment, the loading device 20 issterilized using ethylene oxide sterilization.

The sterile loading device 20 is useful for loading cells, cellclusters, or media into the IID 23. All cell loading steps are performedusing aseptic sterile techniques in a laminar flow hood to maintainsterility and reduce the chances of contamination. The cell pouch of theIID 23 is prepared from semipermeable membranes that may be eitherhydrophilic or hydrophobic in nature. If the semipermeable membranes arehydrophilic the following wetting step may be optional, however if thesemipermeable membranes are hydrophobic the following wetting step isrequired to enhance the wetting of the IID 23. The wetting of the IID 23is as follows. Sterile saline is introduced through the first luerfitting 32 on the disk lid 28. The entire cavity 72 of the loadingdevice 20 is filled with saline from an elevated (<3 meters) containerwithout pumps or pressure. Care must be taken not to over pressurize theIID 23. Next, a syringe containing alcohol is then attached to thesecond luer fitting 166 on the junction block 36. Suitable alcoholsinclude, but are not limited to ethanol and isopropanol, and mixturesthereof. In one embodiment, the alcohol is ethanol. In anotherembodiment, the alcohol is isopropanol in a aqueous solution with up to40% of water by volume. The alcohol is injected into the junction block36 which then enters the inlet tube and then wets the cell pouch(semipermeable membranes) of the IID 23. The system is allowed toequilibrate, allowing a sufficient time for the semipermeable membranesto wet with alcohol, such as for about 3 minutes. At least 1 mL of fluidis removed through the second luer fitting 166 on junction block 36 toremove the excess alcohol. The syringe is then removed from the secondluer fitting 166 on junction block 36. The saline source is moved fromthe first luer fitting 32 on the disk lid 28 and transferred to thesecond luer fitting 166 on the junction block 36. A vacuum line issubsequently attached to the first luer fitting 32 on the disk lid 28. Avacuum pressure of up to 200 mm Hg is applied and maintained until atleast about 40 mL of saline passes through the second luer fitting 166on junction block 36, thereby thoroughly rinsing the IID 23 and loadingdevice 20 to remove residual alcohol. All lines are removed from thefirst and second luer fittings 32 and 166 and they are sealed with firstand second luer caps 34 and 40, respectively. The loading device 20 isthen allowed to sit (12-18 hours) at room temperature.

Subsequently, a vacuum line is attached to the first luer fitting 32 onthe disk lid 28 and a cell and media source is attached to the secondluer fitting 166 on junction block 36. A vacuum of up to 200 mm Hg isapplied until the cell and media source is exhausted. The safety pin 50is removed from the junction block 36 and the barb pusher assembly 42 ispushed until the distal face of plunger 182 contacts the proximal faceof the junction block 36. This motion simultaneously advances theplunger stop 184 causing compression of the barb plug 42 and the wirepusher 180 pushes the barb 44 through barb channel 162 on the junctionblock 36, into the inlet tube of the IID 23 and is deployed, therebysealing the inlet tube of IID 23. Upon releasing the plunger 182, thebarb pusher assembly 46 springs back slightly, such that the wire pusher180 does not extend beyond the distal end of junction block 36 and isout of the pathway of the blade 110 of blade ring assembly 24. Theloading device 20 is then packaged for transport in a manner whichpreserves sterility of the exterior of the assembly. In one embodiment,the loading device 20 is stabilized in a thermoform mold by snapping thefeet 78 within the mold, which is then followed by enclosing in asterile package. The packaged loading device 20 is then transported tothe point of use while maintaining sterility of the assembly. In oneembodiment, the packaged loading device 20 is transported under suitableconditions to maintain viability of the cells therein. A suitableshipping temperature may be determined by the skilled artisan and isdependent upon the cell. The loading device 20 is introduced into thesterile field and removed from sterile packaging. The loading device 20is gripped on the grooves 130 on the disk lid outer wall 128 of the disklid 28 with one hand and the other hand grips the handle 74. The disklid 28 is twisted counter-clockwise thereby rotating the blade ringassembly 24 and cutting the inlet tube flush with the end of the cellpouch of IID 23, while simultaneously removing the disk lid 28. The IID23 then may be presented to the surgeon for implantation.

The loading device 20 may be adapted for the size of the IID 23. Morespecifically, the loading device 20 may be adapted to hold more media tomeet the needs of the increased number of cells in a larger IID 23. Anexploded view of base 52 and support plate 54 is shown in FIG. 13. Base52 is deeper as shown in comparison to base 22 described above, toaccommodate more media. Due to the depth of base 52 an additionalcomponent, a support plate 54, is required and described in detailbelow.

Several views of base 52 are shown in FIGS. 14, 15, and 16. Base 52 hasbase surface 218 and base wall 220 therearound. The base surface 218 andbase wall 220 form a cavity 228 as shown. Base wall 220 includes, baseinner wall 222 and base outer wall 224, with an O-ring channel 226formed in the top surface of the base wall 220. The base wall 220 has aninlet tube conduit 250 on the base inner wall 222 and exiting on thebase outer wall 224 (see FIG. 16). Inlet tube conduit 250 is positionedon the base wall 220 such that when the IID 23 is seated on the supportplate 54, the inlet tube of the IID 23 extends through the inlet tubeconduit 250. Base 52 also includes at least one junction block flange230, a plurality of feet 232, a plurality of tab ramps 234, a tab rampstop 236, and a snap lid stop 238. The junction block flange 230 islocated below the top edge of base outer wall 224 and extendingoutwardly with inlet tube conduit 250 approximately centered within. Thejunction block flange 230 has two flange sides 240, one flange base 242between the flange sides 240, and notch 244 within flange base 242. Theplurality of feet 232 extend outwardly from the base outer wall 224, andpreferably are located at the intersection of the base bottom surface252 (see FIG. 15) and the base outer wall 224 and are uniformlydistributed around the circumference of the base 52 as shown. In oneembodiment, there are at least two feet 232. In another embodiment,there are four feet 232, but any convenient number may be used.Similarly, there are a plurality of tab ramps 234 located at the topedge of the base outer wall 224 extending outwardly from base outer wall224 and uniformly distributed about the circumference of the base 52 asshown, with the first tab ramp 246 aligned with one flange side 240 andthe last tab ramp 248 having a tab ramp stop 236 extending downwardly(see FIG. 15). The tab ramps 234 increase in width in the clockwisedirection such that when the tab ramps 234 are engaged by snaps 156 ofsnap lid 30 as the disk lid 28 is rotated clockwise; simultaneously theO-ring 26 forms a seal between the disk lid 28 and base 52 such thatfluids may not leak out of the base 52. The tab ramp stop 236 (see FIG.15) prevents excessive clockwise rotation of the disk lid 28 and snaplid 30, thereby preventing the snaps 156 of snap lid 30 from disengagingfrom the tab ramps 234 on base 52. In one embodiment, there are at leastfour tab ramps 234. In another embodiment, there are six tab ramps 234.The snap lid stop 238 is aligned with one flange side 240 and the topedge of the base outer wall 224. Furthermore, the snap lid stop 238 ispositioned between the last tab ramp 248 and the junction block flange230, such that the snap lid stop 238 limits counter-clockwise rotationof the snap lid 30 and disk lid 28, thereby preventing the snaps 156 onsnap lid 30 from re-engaging the adjacent tab ramp 234 and enablingopening of the loading device 20 when the loading device 20 is beingopened to gain access to the IID 23.

An alternate top perspective view of base 52 is shown in FIG. 16. Base52 has a plurality of support ribs 256 extending upwardly from basesurface 218 and connected fixedly to base surface 218 and base innerwall 222. The number of support ribs 256 is in an amount sufficient tohold support plate 54 elevated in the base 52 without tilting and theheight of support ribs 256 are such that the IID 23 is held in line withinlet tube conduit 250. The support ribs 256 are uniformly distributedaround the circumference of the base 52 as shown, beginning with firstsupport rib 258 located under inlet tube conduit 250 and having supportrib notch 260 molded into the top surface of first support rib 258. Inone embodiment, there are at least four support ribs 256. In anotherembodiment, there are at least six support ribs 256 but any convenientnumber may be used.

FIG. 15 shows a top perspective view of base 52. Handle 254 may beformed, for example by molding, into base bottom surface 252. Handle 254is useful for stabilizing the loading device 20, for example forstabilizing within the packaging, and providing features with which tograsp the loading device 20 when opening to retrieve the IID 23.

A top perspective view of support plate 54 is shown in FIG. 17. Supportplate 54 removably connects with base 52 by resting on support ribs 256and against base inner wall 222. Support plate tab 304, located onbottom side of support plate 54, removably seats in support rib notch260 on first support rib 258. Support plate 54 has plate surface 308 andblade ring channel 296 therearound, which further has a blade ring stop298, and a blade ring support 300 within blade ring channel 296. Theblade ring support 300 is approximately aligned with flange side 240 andsnap lid stop 238 when loading device 20 is assembled. The blade ringstop 298, is positioned in the blade ring channel 296, such that theblade ring end 116 sits against the blade ring stop 298 and the bladeend 118 sits on the blade ring support 300. Plate surface 308, whilesubstantially flat, slopes down from high point 310 and angled towardIID receiver 302. The slope is selected so that it maintains a uniformspacing with the lid floor bottom 144 of the disk lid 28, when theloading device 20 is assembled. IID receiver 302 is located on platesurface 308 and is a cut out that provides relief (or clearance space)for the attachment point between the inlet tube of the IID 23 and thecell pouch of the IID 23 such that the inlet tube of the IID 23 is notcompressed during assembly of the loading device 20. Support plate 54has a plurality of plate holes 306 vertically through the height ofsupport plate 54. The plate holes 306 are selected as to sufficientlyallow fluid and gas exchange above and below support plate 54, whilesupporting the IID 23 on plate surface 308.

The remainder of the loading device 20 components are assembled aspreviously described above for loading device 20.

The loading device 20 is useful to load an immune-isolation device(“IID”) with cells or cell clusters while minimizing the opportunitiesfor contamination due to manual manipulation. Previously, the processfor loading cells, cell clusters, media, or wetting agents into thedevice required the user to manually handle the IID 23, includingdirectly touching the inlet tube or the cell pouch of the IID 23. Theinvention allows the user to handle the loading device 20 without evertouching the IID 23, until the IID 23 is purposely removed from theloading device 20 for implantation. The IID 23 is not removed from theloading device 20 until the point of use.

Furthermore, the loading device 20 is also useful as the packaging forthe IID 23. The feet 78 (or 232) secure the loading device 20 in thesecondary packaging. At the point of use, the loading device 20 isremoved from the secondary packaging, the disk lid 28 is gripped andturned counter-clockwise which simultaneously opens the loading device20 and the blade 110 trims the inlet tube of the IID 23 to be flush withthe proximal end of the cell pouch of the IID 23 (not shown). The IID 23is then carefully removed from the loading device 20 and implanted atthe point of use.

EXAMPLES Example 1

This example describes the use of the loading device 20 to load cells orcell clusters into the IID 23. A loading device 20 is assembled asdescribed above and sterilized using ethylene oxide sterilization. Allsteps below are performed using aseptic sterile techniques in a laminarflow hood unless stated differently. First, the IID 23 is treated toenhance wetting of the IID 23. Sterile saline is introduced through thefirst luer fitting 32 on the disk lid 28. The entire cavity 72 of theloading device 20 is filled with saline from an elevated (<3 meters)container without pumps or pressure. Care must be taken not to overpressurize the IID 23. A syringe containing ethyl alcohol is thenattached to the second luer fitting 166 on junction block 36. Ethanol isinjected into the junction block 36 which wets the semipermeablemembranes of the IID 23. The system is allowed to equilibrate for about3 minutes then at least 1 mL of fluid is removed through second luerfitting 166 on junction block 36. The syringe is then removed from thesecond luer fitting 166 on junction block 36. The saline source is movedfrom the first luer fitting 32 on the disk lid 28 to the second luerfitting 166 on junction block 36 and simultaneously a vacuum line isattached to the first luer fitting 32 on the disk lid 28. A vacuumpressure of up to 200 mm Hg is applied and maintained until 40 mL ofsaline passes through the second luer fitting 166 on junction block 36.All lines are removed from the first and second luer fittings 32 and 166and they are sealed with first and second luer caps 34 and 40,respectively. The loading device 20 then allowed to sit (12-18 hours) atroom temperature.

Subsequently, a vacuum line is attached to the first luer fitting 32 onthe disk lid 28 and a cell and media source is attached to the secondluer fitting 166 on junction block 36. A vacuum of up to 200 mm Hg isapplied until the cell and media source is exhausted. The safety pin 50is removed from the junction block 36 and the barb pusher assembly 46 ispushed until the distal face of plunger 182 contacts the proximal faceof the junction block 36. This motion simultaneously advances theplunger stop 184 causing compression of the barb plug 42 and the wirepusher 180 pushes the barb 44 through barb channel 162 on the junctionblock 36, into the inlet tube of the IID 23 and is deployed, therebysealing the inlet tube of IID 23. Upon releasing the plunger 182, thebarb pusher assembly 46 springs back slightly, such that the wire pusher180 does not extend beyond the distal end of junction block 36 and isout of the pathway of the blade 110 of blade ring assembly 24. Theloading device 20 is then packaged for transport in a manner whichpreserves sterility of the exterior of the assembly. The packagedloading device 20 is then transported to the point of use again whilemaintaining sterility of the assembly. The loading device 20 is broughtinto the sterile field and opened counter-clockwise to present the IID23 for implantation. The act of opening the loading device 20 cuts theinlet tube of the IID 23 flush with the end of the cell pouch of IID 23and allows the cell loaded IID 23 to be retrieved for implantation.

What is claimed is:
 1. A method of preparing immune-isolation devices,comprising: providing a loading system comprising: a base having a basebottom surface and a base wall extending from the base bottom surface toform a cavity, an inlet conduit positioned on the base and extendingthere through into the cavity, and a disk lid removably attachable tothe base to seal the cavity; coupling an immune-isolation devicecomprising an inlet tube attached to a pouch, to the inlet conduitpositioned on the base within the cavity; sealing the cavity with thedisk lid; filling the pouch of the immune-isolation device with cellsvia the inlet conduit; filling the cavity with cell media; and sealingthe inlet tube.
 2. The method of claim 1, further comprising wetting theimmune-isolation device prior to filling the pouch.
 3. The method ofclaim 1, further comprising sterilizing the loading system.
 4. Themethod of claim 3, wherein sterilizing comprises at least one of gammasterilization, e-beam sterilization, and ethylene oxide sterilization.5. The method of claim 2, further comprising introducing saline throughan opening in the disk lid.
 6. The method of claim 5, further comprisingintroducing saline without pumps or pressure.
 7. The method of claim 5,further comprising introducing an alcohol through the inlet conduit. 8.The method of claim 7, further comprising allowing the alcohol andsaline to equilibrate.
 9. The method of claim 7, further comprisingremoving a portion of the alcohol through the inlet conduit.
 10. Themethod of claim 9, further comprising coupling a saline source to theinlet conduit, and coupling a pump to a hole in the disk lid.
 11. Themethod of claim 10, further comprising drawing saline from the salinesource by reducing pressure with the pump.
 12. The method of claim 11,further comprising sealing the loading system, and allowing the loadingsystem to equilibrate.
 13. The method of claim 11, further comprisingcoupling a cell and media source to the inlet conduit.
 14. The method ofclaim 11, further comprising drawing cell and media from the cell andmedia source by reducing pressure with the pump.
 15. The method of claim14, further comprising sealing the immune-isolation device.
 16. Themethod of claim 15, wherein sealing the immune-isolation devicecomprises inserting a barb into the inlet tube with a plunger pusherassembly.
 17. The method of claim 16, engaging a first feature on thebase bottom surface outside the cavity with a second feature such thatthe loading system is stabilized during transportation.
 18. The methodof claim 16, wherein the loading system further comprises a blade havingan edge slidably disposed within the cavity of the base and configuredto slide in front of the inlet conduit, and sliding the blade to cut theinlet tube of the immune-isolation device.
 19. The method of claim 18,wherein the blade is part of a blade assembly slidably located in thecavity of the base, and wherein the blade assembly is configured tointeract ratchedly with the disk lid.
 20. The method of claim 19,wherein removing the disk lid exposes the immune-isolation device. 21.The method of claim 20, wherein removing the disk lid facilitates thesliding of the blade to cut the inlet tube of the immune-isolationdevice.